Earlier versions of this R01 grant focused on the role of transcription factors in mediating depression-related behavioral abnormalities in animal models. We were the first to implicate CREB in stress models and antidepressant responses. More recently, over the past 10 years, we have similarly defined the actions of delta-FosB in determining an animal's susceptibility vs. resilience to chronic stress. We have also used a range of genome-wide assays to define the target genes of these transcription factors. These evolving datasets suggest the central involvement of glutamatergic neurotransmission within the nucleus accumbens (NAc), a key brain reward region, in governing these distinct responses to stress. Thus, for this competitive renewal application, we propose to utilize this novel insight to define how altered glutamatergic signaling in NAc controls stress susceptibility vs. resilience. We use state-of-the-art optogenetic tools to activate or suppress specific glutamatergic inputs to NAc and investigate the effect of these manipulations on both the development of stress-related behavioral abnormalities as well as their expression .We present robust preliminary evidence that different glutamatergic inputs alter stress vulnerability in very different ways. For example, acute optogenetic activation of the prelimbic prefrontal cortex (PFC) promotes resilience, while acute activation of the ventral subiculum (vSUB) or medial thalamus promotes susceptibility. As another example, induction of long-term depression (LTD) specifically at vSUB synapses dramatically enhances resilience, while LTD at infralimbic PFC synapses may enhance susceptibility. These data set the stage for a uniquely comprehensive analysis of how different glutamatergic inputs to NAc differentially control stress responses. The second part of this R01 investigates the role of several prominent target genes, arising from our genome-wide assays and not previously implicated in stress responses, in mediating post- and presynaptic forms of glutamatergic plasticity in NAc. Together, the proposed studies will shed fundamental light on circuit-level mechanisms in stress susceptibility and resilience, and validate a series of new targets for the development of better treatments for depression and other stress-related disorders.